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In contrast to seasonal outbreaks of influenza, pandemics occur when a new subtype or strain of the influenza virus develops, to which humans have little pre-existing immunity. The three pandemics that occurred during the 20th century spread rapidly and globally, and resulted in many deaths. More

Viruses and Evolution

This diagram shows how different flu viruses exchange genetic material in a process known as antigenic shift.

CDC/Doug Jordan, M.A.

The outer coating of this influenza virus has been cut away, revealing its contents.

Copyright Dennis Kunkel Microscopy, Inc.

Influenza A virus, transmission electron micrograph, x31,710

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Just as natural selection has shaped the evolution of humans, plants, and all living things on the planet, natural selection shapes viruses, too. Though viruses aren’t technically living – they need a host organism in order to reproduce – they are subject to evolutionary pressures.

The human immune system uses a number of tactics to fight pathogens. The pathogen’s job is to evade the immune system, create more copies of itself, and spread to other hosts. Characteristics that help a virus do its job tend to be kept from one generation to another. Characteristics that make it difficult for the virus to spread to another host tend to be lost.

Take, for example, a virus that has a mutation that makes it particularly deadly to its human host and kills the host within a few hours of infection. The virus needs a new, healthy host for its descendents to survive. If it kills its host before the host infects others, that mutation will disappear.

One way hosts protect themselves from a virus is to develop antibodies to it. Antibodies lock onto the outer surface proteins of a virus and prevent it from entering host cells. A virus that appears different from other viruses that have infected the host has an advantage: the host has no pre-existing immunity, in the form of antibodies, to that virus. Many viral adaptations involve changes to the virus’s outer surface.

Below we look at two special cases in viral evolution: how evolution occurs in influenza viruses and in the human immunodeficiency virus (HIV, the virus that causes AIDS). Both of these viruses are RNA viruses, meaning that their genetic material is encoded in RNA, not DNA. DNA is a more stable molecule than RNA, and DNA viruses have a proofreading check as part of their reproductive process. They manage to use the host cell to verify viral DNA replication. If the virus makes a mistake in copying the DNA, the host cell can often correct the mistake. DNA viruses, therefore, do not change, or mutate, much. RNA, however, is an unstable molecule, and RNA viruses don’t have a built-in proofreading step in their replication. Mistakes in copying RNA happen frequently, and the host cell does not correct these mistakes. RNA virus mutations are frequent and can have important consequences for their hosts.

Influenza Viruses

Influenza viruses are simple entities belonging to one of three types: A, B, or C. They consist of no more than seven or eight RNA segments enclosed within an envelope of proteins. Mutations in viral RNA and recombinations of RNA from different sources lead to viral evolution.

Antigenic Drift

Influenza viruses can evolve in a gradual way through mutations in the genes that relate to the viral surface proteins hemagglutinin and neuraminidase (HA and NA in shorthand). These mutations may cause the virus’s outer surface to appear different to a host previously infected with the ancestor strain of the virus. In such a case, antibodies produced by previous infection with the ancestor strain cannot effectively fight the mutated virus, and disease results. (Hemagglutinin and neuraminidase lend their first initials to flu subtypes. For example, the 2009 influenza pandemic was caused by an influenza A H1N1 virus.) As mutations accumulate in future generations of the virus, the virus “drifts” away from its ancestor strain.

Antigenic drift is one reason that new flu vaccines often need to be created for each flu season. Scientists try to predict which changes are likely to occur to currently circulating flu viruses. They create a vaccine designed to fight the predicted virus. Sometimes the prediction is accurate, and the flu vaccine is effective. Other times the prediction misses the mark, and the vaccine won’t prevent disease.

Antigenic Shift

Antigenic shift is a process by which two or more different types of influenza A combine to form a virus radically different from the ancestor strains. The virus that results has a new HA or NA subtype. Antigenic shift may result in global disease spread, or pandemic, because humans will have few or no antibodies to block infection. However, if the new influenza A subtype does not easily pass from person to person, the disease outbreak will be limited.

Antigenic shift occurs in two ways. First, antigenic shift can occur through genetic recombination, or reassortment, when two or more different influenza A viruses infect the same host cell and combine their genetic material. Influenza A viruses can infect birds, pigs, and humans, and major antigenic shifts can occur when these virus types combine. For example, a pig flu virus and a human flu virus could combine in a bird, resulting in a radically different flu type. If the virus infects humans and is efficiently transmitted among them, a pandemic may occur.

Second, an influenza A virus can jump from one type of organism, usually a bird, to another type of organism, such as a human, without undergoing major genetic change. If the virus mutates in the human host so that it is easily spread among people, a pandemic may result.

In all cases, antigenic shift produces a virus with a new HA or NA subtype to which humans have no, or very few, preexisting antibodies. Once scientists are able to identify the new subtype, a vaccine can generally be created that will provide protection from the virus.

Why does antigenic shift occur only with influenza A, and not influenza B and C? Influenza A is the only influenza type that can infect a wide variety of animals: humans, waterfowl, other birds, pigs, dogs, and horses. Recombination possibilities, therefore, are very low or nonexistent with influenza B and C.

A pandemic had the potential to occur in the bird flu outbreaks in 2003 in Asia. An H5N1 influenza A virus spread from infected birds to humans, resulting in serious human disease. But the virus has not evolved to be easily spread among humans, and an H5N1 pandemic has not occurred.

HIV

The virus that causes Acquired Immune Deficiency Syndrome (AIDS) is a highly genetically variable virus, for several reasons. First, it reproduces much more rapidly than most other entities. It can produce billions of copies of itself each day. As it makes rapid-fire copies of itself, it commonly makes errors, which translate into mutations in its genetic code. The more beneficial the mutations are to the virus’s survival, the more likely that mutated virus will be to reproduce itself.

Another cause of the variability in HIV results from the virus’s ability to recombine and form new variants within an individual. This happens when a host cell is infected with two different variations of HIV. Elements of the two viruses may combine to result in a new virus that is a unique combination of the two parents.

The rapid rate of HIV evolution has important consequences. HIV can quickly develop resistance to anti-HIV drugs. Additionally, targeting a vaccine to a rapidly changing virus is challenging. To date, researchers have developed several candidate HIV vaccines, but none has performed well enough in clinical trials to warrant licensure. Read the article Development of HIV Vaccines to learn more about the challenges and promise.

Timeline Entry: 1957Asian Influenza Pandemic

Hilleman and Anthony Payne at a World Health Organization meeting on influenza in Stockholm, 1958

Courtesy of Merck

Maurice Hilleman at Walter Reed Army Medical Center

Footage courtesy of The Vaccine Makers project

Maurice Hilleman discusses the 1957 Asian flu pandemic.

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Maurice Hilleman and his colleagues at WRAIR identified a new influenza A virus, Type A2, Asian influenza, that caused a pandemic.

Hilleman noticed news reports of a severe influenza in Hong Kong. The number of cases and their description led him to think that a new type of influenza was emerging and that a pandemic threatened.

Hilleman and his team obtained a sample of the virus from a U.S. serviceman. They soon determined that most people lacked antibody protection from the new influenza virus. Only a few elderly people who had survived the influenza pandemic of 1889-1890 showed antibody response to the new virus.

Hilleman jump-started vaccine production by sending virus samples to manufacturers and urging them to develop the vaccine in four months. Worldwide, from 1957-1958, about 2 million people died from Asian flu, with about 70,000 deaths in the United States. Some predicted that the U.S. death toll would have reached 1 million without the vaccine that Hilleman called for. Health officials widely credited that vaccine with saving many lives.